Thyroid hormone resistance clinical challenges and genetics (#381)

Thyroid hormone resistance (THR) is characterised by elevated or normal thyroid stimulating hormone (TSH) and elevated thyroid hormones levels (1,2). Most cases are due to a mutation in the thyroid hormone receptor β gene (TRβ)(1,2).

Case description:

A 45 year old female presented for management of thyrotoxic symptoms including paroxysmal atrial fibrillation/flutter (AF). Graves’ disease was diagnosed despite normal TSH with elevated levels of fT4 and fT3, and managed with carbimazole and propranolol. They were discontinued when she developed side-effects with no resolution of her palpitations and TSH increased to 13.3 mU/L. Genetic testing demonstrated a heterozygous TRβ missense mutation: c.805T>A p.Phe269Ile, and in silico analyses were highly suggestive of a deleterious mutation. There was a strong paternal history of abnormal thyroid function tests with an autosomal dominant pattern. Recurrent AF was unresponsive to flecainide and verapamil. A trial of tiratricol (TRIAC) therapy was commenced with symptomatic improvement but no change in thyroid hormone profile or ECG.

Discussion:

Thyroid hormone receptors have a number of α and β isoforms. Thyroid hormone resistance is frequently due to TRβ gene mutations with variable phenotypes. Indicators of hypo- and hyperthyroidism may coexist within one individual(1,3). They may demonstrate a mild hyperthyroid effect on cardiac muscle(7). Patients with hypothyroid symptoms may respond to thyroxine whereas those with hyperthyroid features often respond to beta-blockers. Tiratricol (TRIAC) is a thyromimetic T3 analogue that preferentially acts on the pituitary(1,5) and has been shown to have some clinical benefit in small studies (1,5). Higher doses may provoke thyrotoxic symptoms(6) and long term outcomes are unclear.

Conclusion:

This case demonstrates the complexities of managing THR. Given time, the utility of tiratricol in her case will become clearer.